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U.O. Malattie Infettive, Dipartimento di Medicina dell’Università di Udine – Università di Udine e Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy
U.O. Malattie Infettive, Dipartimento di Medicina dell’Università di Udine – Università di Udine e Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy
Correspondence to: Lipoapheresis Unit and Reference Center for Inherited Dyslipidemias, Fondazione Toscana Gabriele Monasterio, Via Moruzzi, 1, 56124 Pisa, Italy.
Adrenomedullin (ADM), a new member of adipokine family, is secreted by endothelial cells and smooth vasal musculature, is involved in systemic circulation control, performs an autocrine/paracrine vasoactive action and has a role in vascular endothelial function [
Moreover, ADM have important physiologic effects on cardiovascular system because the plasma concentrations of ADM are increased in several cardiac diseases as heart failure. The actions of ADM are generally protective and beneficial to organs and tissues subjecting that increased ADM expression or activity could act as a compensatory response to end-organ injury [
Prognostic value of midregional pro-adrenomedullin in patients with acute myocardial infarction: the LAMP (Leicester Acute Myocardial Infarction Peptide) study.
Mid Regional pro-ADM (MR-proADM) is a stable ADM surrogate marker, is promising novel biomarker used, alone or in combination with procalcitonin, to confirm the presence of infection or as prognostic factor in patients with sepsis and septic shock [
Prognostic value of midregional pro-adrenomedullin in patients with acute myocardial infarction: the LAMP (Leicester Acute Myocardial Infarction Peptide) study.
We know that dyslipidemia is widely accepted as one of the major risk factors in cardiovascular disease and hypercholesterolemia has shown to impair endothelium [
Aim of this pilot study is to evaluate the MR-proADM as new biomarker of endothelial restoration in patients with Familial Hypercholesterolemia (FH) disease on chronic LA.
We evaluate 32 patients (mean age 63 ± 11 years, male 69 %) with FH on maximally tolerated lipid lowering therapy and chronic LA (9 ± 8 years). No patients had relevant comorbidity as diabetes mellitus, arterial hypertension, current smoking exposure and renal failure. Lp(a)-hyperlipoproteinemia (defined as concentration >50 mg/dl) was present in 26/32 (81 %) subjects, as 27/32 (84 %) had previous ischemic heart disease (IHD). The clinical characteristics of patients are summarized in Table 1.
Lipoprotein apheresis. LA treatments were performed by dextran-sulphate absorption from plasma (Liposorber®-LA MA-03 systems; Kaneka, Osaka, Japan; 22/32 patients), heparin-induced LDL precipitation apheresis (HELP®, Plasmat Futura®; B. Braun, Melsungen, Germany; 7/32 patients) or immunoadsorption (TheraSorb™ – LDL pro Adsorber, Miltenyi biotec, Bergisch Gladbach, Germany; 2/32 patient) in agreement with guidelines and manufacturer’s instructions.
Laboratory methods. MR-proADM plasma concentrations were measured in an automated Kryptor analyzer, using TRACE technology (Kryptor; BRAHMS, Hennigsdorf, Germany). The lower detection limit was 0.05 nmol/L, while the limit Of Quantitation (LOQ) was 0.23 nmol/L; the cut-off for physiological concentration was pointed at < 0.56 nmol/L [
]. Lipid profile were evaluated using routine certified diagnostic methods. Blood collection was performed before, an immediately after, the LA treatment.
Statistical analysis. Data were expressed as mean ± standard deviation, median and interquartile range or proportions, as appropriate. Comparisons were performed with paired sample t-test, Wilcoxon test or Chi-square test with continuity correction. Furthermore, Pearson correlation coefficient, between Δ MR-proADM and Δ LDL cholesterol or Δ HDL cholesterol, was computed. The analysis was accomplished with R statistical software (R, version 2.11.1, 2010). A p value < 0.05 was considered statistically significant.
FH subjects undergoing LA treatment are a paradigmatic clinical model where lipids concentrations rapidly plunge from extremely high to extremely low levels after selective removal (see Table 2). Pearson analysis showed a significant correlation between Δ MR-proADM – Δ LDL cholesterol (r − 3.56; p 0.039) and between Δ MR-proADM – Δ HDL cholesterol (r 0.446; p 0.008 – see Fig. 1).
Table 2Comparison between lipid concentrations and MR-proADM before (Pre-LA) and after lipoprotein apheresis (Post-LA).
Pre-LA
Post-LA
p
Total cholesterol (mg/dl)
205 ± 71
90 ± 28
< 0.001
Triglycerides (mg/dl)
175 ± 12
53 ± 37
< 0.001
HDL cholesterol (mg/dl)
50 ± 13
43 ± 11
< 0.001
LDL cholesterol (mg/dl)
123 ± 65
37 ± 26
< 0.001
Lipoprotein(a) (mg/dl)#
100 [76 – 129]
24 [16–33]
< 0.001
MR-proADM (nMol/L)
0.83 ± 0.56
0.79 ± 0.50
0.578
# - evaluate on 26/32 subjects with Lp(a)-hyperlipoproteinemia (definite as concentration >50 mg/dl).
Furthermore, in one explicative case, was analyzed the MR-proADM time course after a lipoprotein apheresis treatment. To note that lipids parameters are in agreement with MR-proADM value secondary to a rapid restoration in HDL cholesterol and to a progressive increase in LDL cholesterol (Fig. 2).
Fig. 2Example of MR-proADM, LDL cholesterol and HDL cholesterol time course after a lipoprotein apheresis treatment.
Prognostic value of midregional pro-adrenomedullin in patients with acute myocardial infarction: the LAMP (Leicester Acute Myocardial Infarction Peptide) study.
In this pilot experience the MR-proADM modification mirrored the changes in the lipid concentrations carried out by LA. It is known that LA is able to reduce LDL cholesterol levels, but also affect HDL levels, composition and serum cholesterol efflux capacity [
]. Correlation between Δ MR-proADM and Δ LDL or Δ HDL cholesterol could provide similar indications such previous experience with soluble cell adhesion molecule [
There is a main limitation to this study: our sample is made up of subject on chronic LA treatment, this treatment contributes to the stabilization of atherosclerosis and leads to a progressively reduction in C-reactive protein [
], an aspect that could be underestimate the LA effect on the MR-proADM concentrations. Furthermore, the small sample size could non-furnish the necessary power to our model.
We evaluate with caution our results, and further studies will be needed to evaluate if the modulation of MR-proADM plasma levels can be useful for recognition of the “healthy endothelium” and/or could have a therapeutic impact.
Funding sources
No financial support was received.
Disclosures
CT has received funds for speaking at symposia organized on behalf of Pfizer, Novartis, Merck, Angelini, Thermofischer, Biomerieux, Basilea, Correvio, Zambon, Hikma and Astellas. All other authors: None.
Acknowledgments
The authors are grateful to Mascia Pianelli and Roberta Luciani for the excellent work in the apheresis unit.
References
Del Ry.S.
Cabiati M.
Bianchi V.
Caponi L.
Di Cecco P.
Marchi B.
et al.
Mid-regional-pro-adrenomedullin plasma levels are increased in obese adolescents.
Prognostic value of midregional pro-adrenomedullin in patients with acute myocardial infarction: the LAMP (Leicester Acute Myocardial Infarction Peptide) study.
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